A cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases

Abstract Background Allergic diseases, including respiratory and food allergies, as well as allergic skin conditions have surged in prevalence in recent decades. In allergic diseases, the gut microbiome is dysbiotic, with reduced diversity of beneficial bacteria and increased abundance of potential pathogens. Research findings suggest that the microbiome, which is highly influenced by environmental and dietary factors, plays a central role in the development, progression, and severity of allergic diseases. The microbiome generates metabolites, which can regulate many of the host’s cellular metabolic processes and host immune responses. Aims and Methods Our goal is to provide a narrative and comprehensive literature review of the mechanisms through which microbial metabolites regulate host immune function and immune metabolism both in homeostasis and in the context of allergic diseases. Results and Discussion We describe key microbial metabolites such as short‐chain fatty acids, amino acids, bile acids and polyamines, elucidating their mechanisms of action, cellular targets and their roles in regulating metabolism within innate and adaptive immune cells. Furthermore, we characterize the role of bacterial metabolites in the pathogenesis of allergic diseases including allergic asthma, atopic dermatitis and food allergy. Conclusion Future research efforts should focus on investigating the physiological functions of microbiota‐derived metabolites to help develop new diagnostic and therapeutic interventions for allergic diseases.


| Histamine
Histamine is generated by microbes following decarboxylation of the amino acid histidine, which can activate human histamine receptors similar to host-derived histamine. 44High histamine levels are present in certain foods such as wine, tuna, mackerel, anchovy, spinach, sausage, dairy products, and fermented foods. 45,468][49][50] An increased abundance of histamine-secreting microbes, especially Morganella morganii, was observed within the gut of adult asthma patients, while histamine secretion from gut microbes could influence immune responses in the murine lung. 27,51
regulatory macrophage (M2b) phenotype. 56Ursodeoxycholic acid (UDCA) induced immunosuppressive phenotype on dendritic cells via nuclear FXR receptor. 57Bile acids can also modulate Treg cell populations.IsoalloLCA enhanced CD4 þ T cell differentiation to Treg cells in vitro. 58Supplementation with either primary or secondary BAs increased colonic RORγ þ Treg cell counts and decreased colitis symptoms in mice. 59

| Sphingolipids
Sphingolipids are yet another group of microbial metabolites originating from both host and microbiome metabolism. 60The main dietary sources of sphingolipids are dairy products, eggs, soybeans, and fruits. 61In eukaryotic cells, they are structural membrane components that also function as signaling molecules. 62Out of gut commensals, Bacteroides is known to produce sphingolipids as part of its membrane. 63Bacteroides fragilis-derived sphingolipid alpha-galactosylceramide affected the numbers and function of natural killer T cells in a murine colitis model. 64

| Polyamines
Another microbiota-derived immunomodulatory compound is polyamines, produced by transamination of ingested amino acids by gut microbiome, including Bifidobacterium angulatum, B. animalis, B. faecale, and B. longum. 65,66The primary exposure to polyamines commences through breast milk and formula milk, subsequently to cereals, legumes, soy derivatives, as well as animal-derived sources such as beef, pork, chicken, and sausages. 67Spermine and spermidine treatment decreased LPS-induced production of pro-inflammatory cytokines in macrophages. 68In vitro, spermidine induced differentiation of naive T cells into regulatory phenotype 69

| P-cresol sulfate
Finally, the immunomodulatory potential of L-tyrosine metabolite, pcresol sulfate (PCS) has recently been demonstrated.PCS acted on airway epithelial cells to uncouple EGFR-TLR-4 cross-talk, thereby attenuating CCL20 secretion in response to LPS or HDM. 71

| Innate immune cells
Among the metabolites synthesized by the host or transformed by the microbiome, SCFAs, bile acids, and tryptophan catabolites are major signal molecules that are involved in intestinal epithelial integrity. 72SCFAs activate GPR41 and GPR43 on intestinal epithelial cells, inducing the production of cytokines (TNF-α and IL-6) and chemokines (CXCL1 and CXCL2), which promote the recruitment of neutrophils and activation of effector T cells. 73This leads to the induction of protective immune responses against pathogens.SCFAs promote the expression of antimicrobial molecules, RegIIIγ and βdefensins, through GPR43, which are vital for the maintenance of intestinal homeostasis. 74milarly, indole, a tryptophan metabolite, induces epithelial cell tight junction resistance, inhibits IL-8 secretion and TNF-α mediated NF-κB activation, and reduces the expression of proinflammatory cytokines and chemokines. 75Indole and its derivatives exert biological functions through aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and toll-like receptor 4 (TLR4) expressed in various cells within the gut. 76The activation of AhR attenuates increased paracellular permeability of the intestinal epithelium and ameliorates localization of tight junction proteins. 77AhR deficiency enhances airway inflammation, mucus production, airway hyperresponsiveness, and remodeling in the chronic asthma model. 78Indole-mediated activation of PXR is also an essential regulator of TLR4-mediated control of the intestinal barrier function, and the deficiency of PXR decreases intestinal homeostasis and induces inflammation. 79le acids play an essential role in many aspects of the maintenance of intestinal barrier integrity. 80Alteration of the bile acid profile changes the intestinal permeability and affects the barrier function by regulating tight junction protein expression. 80High-fat diet, which profoundly affects both the composition of the microbiota and of the bile acids pool, was shown to increase mucosal permeability by reducing the expression of occludin, antimicrobial peptide RegIIIβ, and IL-22. 81

| Adaptive immune cells
SCFAs facilitate naïve T-cell differentiation into the generation of Th1 and Th17 cells during active immune responses. 82Moreover, SCFA and its receptor-signaling pathway induce the proliferation of Treg cells and upregulate the secretion of anti-inflammatory cytokines, thereby suppressing allergic immune response. 83Innate lymphoid cells (ILCs) and CD4 þ T cells produce IL-22, which plays an important role in intestinal immunity.A study has shown that SCFA butyrate escalates the production of IL-22 by CD4 þ T cells and ILCs to maintain intestinal homeostasis. 84Butyrate also inhibits IL-5 and IL-13 production to modulate ILC2-driven airway hyperresponsiveness and airway inflammation. 85SCFAs have been found to protect against food allergies by promoting immune tolerogenic mechanisms, including the maintenance of intestinal Treg cells and luminal IgA production. 83,86Bile acid metabolites control Th17 and Treg cell differentiation in the intestinal lamina propria. 58Secondary bile acids have been reported to induce Foxp3 expression and RORγ þ regulatory T-cell production in murine colitis model. 59 B cells, SCFAs are the major metabolites that regulate both mucosal and systemic antibody responses. 87SCFAs boost cellular metabolism and provide building blocks that support B cell activation, differentiation, and antibody production.SCFAs also control gene expression required for B-cell differentiation. 87In allergic asthma, butyrate and propionate downregulate expression of activationinduced cytidine deaminase (AID) and B lymphocyte-induced maturation protein 1 (Blimp-1), thereby reducing the rate of B-cell class switching and the levels of circulating IgG1, IgA, and IgE. 88Patients suffering from rheumatoid arthritis were demonstrated to have lower levels of SCFAs, and the administration of these metabolites in vivo improved the symptoms of this condition. 89yptophan metabolites have both stimulatory and inhibitory effects on B cells.I3C can regulate B-cell function by decreasing mature B cells and certain autoantibodies. 90Furthermore, IDOgenerated metabolites inhibit lipopolysaccharide-induced antibody secretion and inhibit B-cell apoptosis. 91IDO deficiency is associated with elevated levels of IgA that cross-reacts with the enteric pathogen Citrobacter rodentium, demonstrating the role of IDO in the regulation of immunity to the gut microbiome. 91nally, B cells contribute to maintaining bile acid homeostasis in the gut; consequently, impaired humoral immunity can disrupt this balance, leading to inflammatory gut diseases. 92Research suggests that the severity of intestinal inflammatory disease is influenced by both B cells and bile acids. 93

| MICROBIAL METABOLITES IN THE IMMUNE METABOLISM OF THE HOST
Immune metabolism is a term encompassing all intracellular biochemical processes leading to the proliferation, activation, and function of human immune cells. 94The focus of this developing research is to uncover how metabolic pathways govern and contribute to the regulation of appropriate immune responses within cells of the immune system, collectively known as immune metabolism.Certain metabolic programs support the immune functions of the cells, their differentiation, and phenotypic characteristics and therefore are increasingly recognized as cellular fingerprints, comparatively to cytokine or transcription factor profiles. 94,95However, metabolism far exceeds the complexity of immunological phenotypes.Catabolic processes in the cell are responsible for energy production in the form of ATP.They include cytoplasmic anaerobic glycolysis and mitochondrial tricarboxylic acid (TCA), oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO).Of those, only anaerobic glycolysis and OXPHOS create ATP directly, with OXPHOS being energetically much more efficient, but anaerobic glycolysis being much faster. 94,95These pathways are interconnected with each other via common metabolites.For instance, glycolysis initiated in the cytoplasm after glucose transport creates not only ATP but also pyruvate, which is a substrate of TCA and thus participates in the TCA and OXPHOS, thus being called aerobic glycolysis.ATP in the cell is then used for anabolic needs such as nucleotide, protein, carbohydrates and lipid synthesis.Immune metabolism of the cell is thus finely regulated both intracellularly by expression of enzymes responsible for metabolic pathways, but also by availability of extracellular substrates for these processes, as well as by expression of membrane transporters.
Metabolism of bacteria also enables all of the processes needed for life and function of the bacterial cells and communities, often consisting of the same metabolites as in human cells. 96 addition, the human microbiome supplies unique enzymes and metabolites that aid in breaking down food in the gut and in performing xenobiotic metabolism. 96These microbial bioactive molecules encompass vitamins, amino acids, SCFAs, and other metabolites.These metabolites produced by microbiota, similar to host metabolites, may regulate many of the host cellular metabolic processes, exerting this way potent immunoregulatory functions, 97- 100 presumably by modulating the metabolism of the host immune cells.

| SCFAs
The most studied bacterial metabolites are SCFAs.They induce intestinal macrophages into more OXPHOS-derived energy production 101 and less glycolysis, 101 resulting in enhancement of their antimicrobial activity and increased resistance to enteropathogens.
Importantly, the broad disruption of the intestinal microbiome by antibiotic treatment increases the uptake of amino acids by colonic macrophages followed by the upregulation of the neutral amino acid transporter LAT1 (Slc7A5).After increased amino acids uptake, colonic macrophages increased both mTOR and related glycolysis, as well OXPHOS. 102SCFAs act as inhibitors of HDACs and thus modulate the epigenetic landscape, decreasing NF-kB activation and the production of pro-inflammatory cytokines by dendritic cells, monocytes and macrophages. 97,103,104Similarly, HDACdependent regulation of FOXP3 expression in T regulatory cells have been extensively demonstrated in vitro and in vivo, 36,105 implicating profound metabolic reprogramming of Treg cells, but the exact metabolic pathways are yet to be determined.Moreover, SCFAs might induce direct changes in chromatin organisation by histone propionylation and butyrylation (H3K14pr and H3K14bu), again suggesting involvement of specific metabolic programmes. 106milarly, SCFA recognition by GPR43, GPR41 and GPR109a, which are expressed by numerous cell types, including immune cells and intestinal epithelial cells, 97,107 induces the activation of several intracellular signaling pathways, but metabolic consequences are not yet known.

| Tryptophan derivatives
Another group of metabolites being utilized and produced by intestinal microbiota are derivatives of tryptophan.Tryptophan is metabolised by the kynurenine, serotonin and indole pathways.
Clostridium, Bacteroides, Bifidobacterium and Lactobacillus genera produce tryptophan metabolites. 108,109They may act via AhR receptor, which is widely expressed in various cell types in the gut, lung and skin.Kynurenine metabolism, the major catabolic pathway for tryptophan, ends with the production of kynurenic acid and nicotinamide adenine dinucleotide (NAD þ ), both of which have broad effects on immune metabolism.Especially, NAD þ can act as an energy carrier and also as an enzymatic cofactor, 110 directly influencing metabolic reprogramming.In addition, the intermediate metabolites of this pathway, such as hydroxykynurenine (3HK), 3hydroxyanthranilic acid (3HAA), and quinolinic acid (QA) have diverse effects on mitochondrial functions, influencing mitochondrial dynamics (fusion and fission events), mitochondrial related energy pathways (OXPHOS, TCA, FAO), mitochondrial DNA (mtDNA) stability and mitophagy. 111Main enzymes within the kynurenine pathways, such as indoleamine 2,3-dioxygenase 1, 2 (IDO1,2) and tryptophan 2,3-dioxygenase (TDO2) are expressed in immune cells such as macrophages, 112 dendritic cells (DCs), B cells, 113 and natural killer (NK) cells 114 and T cells. 115Therefore, they may have profound effects on immune cell metabolism, although this has not been assessed systematically.

| Amine oxides
The third group of microbial metabolites are Trimethylamine (TMA) and Trimethylamine N-oxide (TMAO).Several metabolites of this group come from the degradation of ingested small molecules such as choline, L-carnitine, or phosphatidylcholine, which are very common in nuts, meat, eggs, and dairy.TMAO, produced in hepatocytes, upon uptake of bacterial TMA and upregulation of enzyme FMO3, binds to the Protein Kinase RNA-Like ER Kinase (PERK) and can induce the FoxO1 transcription factor in hepatocytes. 116TMAO, produced from TMA was demonstrated to be proatherogenic. 117Increased TMAO concentration impairs pyruvate and fatty acid oxidation in cardiac mitochondria, 118 but not much is known about its influence of the metabolic reprogramming of immune cells.

| Bile acids
Finally, bacteria can transform bile acids, creating a complex pool of secondary bile acids with many physiological functions. 119Interestingly, it was shown that one of the secondary bile acid 3β-hydroxydeoxycholic acids (isoDCA) increased Foxp3 induction in Treg cells by acting on DCs via the FXR receptor, 120 but again the exact pathway is not known.

| Asthma
Asthma is a chronic respiratory disease affecting millions of people worldwide. 121There are multiple clinical phenotypes can be distinguished within asthmatic patients, with 2 endotypes having the highest incidence rate: Th2 low and Th2 high (usually observed in allergic and eosinophilic asthma) profiles.Allergic asthma is a heterogeneous disease characterized by excessive Th2 response of the adaptive immune system and consequent overproduction of proinflammatory cytokines IL-4, IL-5, and IL-13. 122Dietary habits and the composition of the gut microbiota are well known to influence the severity of allergic asthma. 123,124Aside from the gut microbiome, microbes locally inhabiting the airways may also affect asthma outcomes, since airway dysbiosis in asthmatic patients is well documented. 125The airways of asthmatic patients have an increased relative abundance of Proteobacteria (Haemophilus, Neisseria, and Moraxella genera), 126 which might potentiate inflammation through the expression of immunogenic compounds, such as lipopolysaccharides or flagellin. 127,128However, in the complete absence of microbes, asthma is also exacerbated as indicated by enhanced type 2 immunity of germ-free mice, which can be restored by microbiota re-colonization. 129These observations point to the importance of a balanced microbiota composition and microbial metabolites in maintaining lung homeostasis (Figure 2).
Though mechanisms that microbes employ to modulate immunity are numerous, their major mode of action involves the regulation of dendritic cell and T cell function directly in the airways.One way to achieve this is by secreting metabolites that reach distal body organs via circulation.

| SCFAs
In the context of allergic asthma, prime examples are SCFAs, mainly butyrate, acetate, and propionate (Table 2).Butyrate and propionate levels in the feces of 1-year-old children were negatively correlated with the risk of developing asthma at 3-6 years of life. 130 animal models, a high-fiber diet increased the levels of circulating SCFAs and alleviated the severity of allergic airway disease. 36nally, supplementation with either butyrate, acetate, or propionate attenuated inflammation in a house dust mite model of murine asthma. 131

| Tryptophan derivatives
Tryptophan metabolism has been shown to regulate T cell inflammatory responses via the IDO pathway, by increasing tryptophan catabolism to kynurenine and shifting differentiation of naive T cells towards regulatory T cells. 132,133IDO activity is also lowered in the blood of asthmatic children pointing towards the therapeutic potential of tryptophan metabolites and the signaling pathways they trigger. 134In a murine model, the administration of kynurenineinduced IDO activity and attenuated OVA-induced allergic asthma. 132Aside from microbial metabolism of L-tryptophan, commensal bacteria can also secrete D-tryptophan, which was shown to exert anti-inflammatory properties.Oral administration of Dtryptophan downregulated airway hyperresponsiveness and Th2associated immune responses in a murine model of allergic airway inflammation. 22

| Polyamines
Another class of metabolites, concentrations of which are associated with asthma outcomes, are polyamines.The levels of spermidine were shown to be decreased in the BAL but increased in the blood of asthmatic patients with active symptoms. 135,136Mice receiving polyamines (spermidine or spermine) via oral gavage displayed reduced severity of HDM-induced asthma and spermidine administration prevented HDM-induced downregulation of tight junction protein expression. 136

| P-cresol sulfate
Finally, a protective effect of L-tyrosine metabolism was shown in the context of the HDM-induced model of asthma.P-cresol sulfate (PCS), the end-product of microbial metabolism of L-tyrosine, reached the airways through circulation, acted on airway epithelial cells, and reduced the production of a dendritic cell chemoattractant, CCL20.
This resulted in impaired infiltration of dendritic cells into the lung tissue and attenuated type 2 inflammation. 71llectively, the examples described above illustrate the potential of metabolites to influence immunity.In many cases, those metabolites can be produced by both host and microbial cells, and the exact contribution of metabolic pathways regulating each site of the ecosystem remains unknown.Likewise, administered metabolites might also induce tailored changes in the global metabolome profiles and thus, indirectly affect cellular processes.Regulatory networks within this interplay are complex and their deciphering will require efforts from multiple perspectives, ranging from metabolic, immunologic, and microbiologic standpoints.
Nonallergic asthma, which is not triggered by allergies, has been linked to Th1 and/or Th17 cell activation and steroid-resistant neutrophilic inflammation. 137The compositions and metabolites of the gut microbiome are distinct between allergic and non-allergic asthmatics.Metabolomics analysis revealed frequent changes in microbial metabolites and upregulation of histamine in non-allergic asthmatics. 138Obese-related asthma, a phenotype of nonallergic asthma, has been associated with an altered gut microbiota with a particular decrease in the abundance of Akkermansia muciniphila. 139other nonallergic asthma that affects approximately 7% of asthmatic patients is aspirin-exacerbated respiratory disease (AERD). 140pirin and/or NSAIDs can directly impact the composition and function of the gut microbiome or indirectly alter the physiological properties or functions of the host. 141NSAID-induced changes in the microbiome promote the conversion of primary to secondary bile acids, resulting in more damage in the intestinal epithelial cells. 142On the other hand, without changing the bacterial population, celecoxib can decrease butyrate production in a human intestine and ameliorate inflammatory markers including IL-8 and CXCL6 in intestinal cells, indicating the importance of the functional role of microbiome rather than taxonomic diversity. 143

| Atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a chronic, inflammatory skin disease that involves genetic and environmental factors, and immunological responses.The prevalence is higher among young children, and 95% experience an onset below the age of 5. 144,145 Although AD resolves before adulthood, severe ADs with multiple factors such as early onset, filaggrin gene (FLG) mutations, and food allergies may persist into adulthood further developing other-allergic co-morbidities defined as the "atopic march". 146AD T A B L E 2 Clinical relevance of microbiota-derived metabolites in allergic diseases.

Metabolite
Prospective cohort Higher fecal acetic acid during pregnancy is associated with a lower risk of atopic asthma/ wheeze in offspring at age 6.

Case-control
The excretion of sulfated bile acids glycolithocholate, glycocholenate, and glycohyocholate was higher in AW children, whereas tauroursodeoxycholate excretion declined.In the urine of AW children, urobilinogen levels were increased 14-fold.

25
Asthma patients had higher plasma levels of taurocholate and glycodeoxycholate.Patients with high FeNO had higher levels of plasma branched-chain amino acids and bile acids.152 The severity of eczema was associated with decreased butyrate-producing bacteria and microbial diversity.proteins. 147,148in harbors heterogeneous microbial communities that are essential for barrier integrity, and skin and systemic immune homeostasis. 149Skin commensals Staphylococcal epidermis (S. epidermidis) and Staphylococcus hominis (S. hominis) produce antimicrobial peptides against pathogens and can decrease the abundance of S. aureus. 150Increased colonization of S. aureus in the skin of AD patients causes dysbiosis of the cutaneous microbiota and decreases bacterial diversity that is inversely correlated with AD severity. 14,17

| SCFAs
The skin microbiome of AD patients has been shown to have a loss of anaerobic bacteria and a switch from anaerobic to aerobic metabolism. 150,151Anaerobic bacteria in the skin ferment carbohydrates and amino acids, producing lactic acid and other SCFAs that lower the skin's pH. 151This acidic environment helps to protect the skin from infection and inflammation.3][154][155] A dominant gut bacterial species, Faecalibacterium prausnitzii, is a SCFA-producer (in particular butyrate) and has been considered beneficial to gut health.The administration of these bacteria has improved dermatitis score, and scratching behavior, and decreased the levels of IgE and TSLP in vivo. 156wever, enrichment of these species along with decreased levels of butyrate and propionate have also been reported in AD fecal samples. 153The loss of anaerobic bacteria in the skin microbiome of AD patients could explain the disturbed gut microbiome, leading to functional alterations of F. prausnitzii and dysregulation of gut epithelial inflammation in these patients.[159][160]

| Tryptophan derivatives
The skin of AD patients displays a lower level of tryptophan metabolites compared to that of healthy subjects. 24The skin microbiota-derived Trp metabolite, indole-3-aldehyde (IAlD), can inhibit TSLP production in KCs by binding AhR and improving the epidermal barrier of the skin. 24 and increases fecal and serum I3A to reduce AD symptoms. 162These findings suggest that microbial-derived metabolite IAlD has potent protection against AD.
AhR expressed in skin cells also acts as a sensor of environmental chemicals in the skin. 163AhR is activated by various external factors, including air pollutants, coal tar, and tryptophan metabolites that are generated by UV light exposure and/or by microbial tryptamine pathway. 161,164,165The activation of AhR via air pollution induces the expression of type 2 cytokines and the neurotrophic factor artemin, which promote AD symptoms. 166In addition, exposure of normal human epidermal keratinocytes to ozone increases the expression of cytochrome P450 isoforms through an AhR-dependent mechanism, 167 suggesting that the AhR pathway may be involved in coping with the air pollution-mediated damage in the skin.

| Food allergy
Food allergy (FA) is an adverse immune response to food proteins that can cause a range of symptoms from mild to severe.It is a growing problem in the world, affecting an estimated 1 in 10 people. 168IgE-mediated FA disease differs from non-IgE-mediated FA in its pathophysiology.IgE-mediated FA is caused by the activation of the immune system, which results in a Th2 response and the binding of IgE to Fcε receptors on effector cells.This triggers the release of histamine and other inflammatory mediators by mast cells and basophils, leading to the rapid onset of symptoms.In contrast, non-IgEmediated FA has a delayed onset and is characterized by subacute or chronic inflammatory processes in the gut. 169

| SCFAs
The gut microbiome may be involved in the development of food allergies by influencing the production of Treg cells, which play a role in suppressing the immune response to food allergens. 170Promoting food tolerance by the induction of Treg cells can be achieved through microbial production of SCFAs. 1713][174][175][176] Patients with FA has less abundant commensal bacteria and lower levels of SCFAs.This loss of SCFAs can impair the function of the immune system and lead to a reduced ability to develop oral tolerance.In an experimental study, SCFA stimulation and a high-fiber-diet induced the expression of Treg cells and antiinflammatory cytokines, reshaped the gut microbiome, and enhanced oral tolerance. 83,174Several reports investigating the potential benefits of probiotics in FA have been published so far.For example, the formula supplemented with Lactobacillus rhamnosus GG influences the bacterial community composition and butyrate production in infants with FA. 175,176

| Tryptophan derivatives
A growing body of evidence suggests an association between FA and tryptophan metabolites.A study using a murine model has shown an important role of the intestinal microbiome in allergic responses through tryptophan metabolism and the production of indole derivatives. 177These derivatives engage with AhR to induce production of IL-22. 178Of note, IDO activity, as assessed by kynurenine/tryptophan ratio is strongly correlated with tolerance to food allergens despite allergen sensitization. 179

| Bile acids
1][182] BA derivatives are implicated in the regulation of gut microbiome and modulation of colonic RORγ þ Treg cell homeostasis. 59Derivatives of lithocholic acid (LCA), 3-oxoLCA, and isoalloCLA, are involved in controlling host immune responses by modulating the balance of Th17 and Treg cell differentiation. 58In an animal study, food sensitization was mediated by bile acid-activated retinoic acid signaling in DCs, which then promoted the production of food allergen-specific IgE and IgG1. 28

| Sphingolipids
1][182] For example, a recent report identified low levels of serum sphingolipids and ceramids in patients with FA 180 , which is consistent with the protective effect of Bacteroides-derived sphingolipids in sensitized individuals. 181However, certain observations contradict the beneficial role of sphingolipid metabolites in FA because they were also detected in higher concentrations in the serum samples of FA patients. 182Together, these observations indicate that the role of sphingolipids in FA may be more complex.

| CONCLUSIONS
Increased diet diversity and environmental biodiversity may alter the taxonomic composition and metabolites of the gut microbiome, potentially increasing the risk of allergies.The impact of microbiotaderived metabolites on the pathogenesis of immune-mediated disease pathogenesis may be greater than previously appreciated.

T A B L E 1 186 Promoting 71 Histamine H 2 R
Functional role of microbial metabolites.differentiation and production of IgA and IgG via HDAC inhibition 88 Suppressing FcεRI-dependent cytokine release 183 Enhancing FoxP3 þ Treg cell differentiation via HDAC inhibition 184 GPR41, GPR43, and GPR109a Impairing the ability of DC to promote T helper 2 response, reducing ILC2 proliferation and function 85 Enhancing tolerogenic CD103 þ DC function via GPR43 and GPR109a, resulting in induction of oral tolerance to peanut antigens in mice 174 Enhancing the generation of DCs with impaired ability to promote T helper 2 hydrocarbon receptor (AHR) Regulating IgE-mediated responses in human mast cells (OVA challenge) Treg cell differentiation and attenuation of allergic responses 187 Regulating dendritic cell immunogenicity 188 TLR9-induced IDO Promoting IDO dependant immunosuppressive phenotype in pulmonary dendritic cells 23 Indole derivatives Aryl hydrocarbon receptor (AHR) Promoting IL-22 production by innate lymphoid cells 161 Polyamines Spermidine Unknown Promoting immunosuppressive phenotype in dendritic cells 189 Promoting CD4 þ T-cell differentiation towards regulatory phenotype Treg 69 Reducing IL-17 production in T cells 69 Tyrosine p-cresol sulfate (PCS) TLR4-EGFR interaction Reducing CCL20 production in HDM-stimulated airway epithelial cells Inducing IL-10-producing Treg cells and dendritic cells 50

70 F I G U R E 1
and activated indoleamine 2,3-dioxygenase (IDO1)-dependent immunosuppressive signaling in DCs. 39,The interplay of gut microbiota-derived metabolites and the immune system.Short-chain fatty acids, derived from bacterial metabolism of dietary fibers, inhibit inflammation by binding membrane receptors (GPR41, GPR43, GPR109A) or inhibiting histone deacetylases (HDACs).Secondary bile acids, produced by bacterial transformation of primary bile acids, bind, among others, to membrane TGR5 (GPBAR1) or nuclear FXR receptors and inhibit inflammation.Tryptophan metabolites modulate the function of immune cells via aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) receptors.Microbiota-derived histamine modulates immune responses via histamine type 2 receptor (H2R).P-cresol sulfate (PCS), derived from the microbial metabolism of L-tyrosine, uncouples EGFR-TLR-4 crosstalk and attenuates inflammation.Polyamines, generated by the metabolism of ingested amino acids, reduce pro-inflammatory signaling through the receptors/pathways that are still to be determined.Microbiota-derived sphingolipids can modulate immune responses via, among others, Sphingosine-1-phosphate receptors (S1PR) or by interacting with CD1d.

E 2
The function of microbial derived metabolites in different-allergic diseases.In allergic asthma, short-chain fatty acids, indole derivatives, polyamines, L-tyrosine, and histamine have been proven to attenuate lung inflammation by regulating immune cell function and other mechanisms.In atopic dermatitis, short-chain fatty acids and indole derivatives improve the disease severity through regulating the level of immunoglobulin E (IgE) and thymic stromal lymphopoietin (TSLP).In food allergy, short-chain fatty acids, indole derivatives, and bile acid derivatives have shown to be connected to disease pathogenesis by affecting the lymphocyte differentiation and other pathways.The observation on the effects of sphingolipids remains conflicting in different clinical studies.LOSOL ET AL.
model) High-fiber diet increased circulating SCFA levels and protection against allergic inflammation in the lung.36 Oral administration of SCFA reduced the severity of allergic airway inflammation.130 Offspring from high-fat diet mice had higher plasma SCFA, thymic, and peripheral Tregs.190 High-fiber or acetate-feeding suppressed allergic airway disease by enhancing Treg cells and expression of certain genes in the fetal lung linked to the disease.123 Experimental (mouse model), clinical trial & case-control Intestinal helminth infection reduced allergic asthma via alterations in the intestinal microbiota and the increase in SCFA production 191 Fecal acetate levels were low in AW children.The concentration of butyrate was low in the AW mouse group.25 Case-control Reduced acetate and increased caproate were detected in the 3-month fecal samples of children who developed atopic wheeze at age 5. 192 Genes and pathways involved in the metabolism of SCFAs and amino acids were enriched in the asthmatic bronchial microbiome.193 Birth cohort Children with the highest levels of butyrate and propionate in feces at the age of 1 yr had less atopic sensitization and less asthma development between 3 and 6 yrs.Children with the highest levels of butyrate had less FA or AR.
model) TLR9 ligand-induced pulmonary IDO activity inhibited Th2-driven asthma.23 D-tryptophan administration increased lung and gut Tregs, decreased lung Th2 responses, and improved allergic airway inflammation and hyperresponsiveness. 22 Case-control Patients with asthma and AR had higher neopterin, tryptophan, and kynurenine levels, and lower IgE levels and IDO-1 enzyme activity.195 Allergic asthma children had lower IDO levels in the peripheral blood and sputum.IDO levels negatively correlated with FeNO.196 Prospective cohort Pulmonary IDO activity was lower in patients with allergic asthma.Systemic tryptophan and its catabolites were higher in these patients.Systemic quinolinic acid and tryptophan were associated with ECP and eosinophils in BAL fluid and peak asthma symptom scores after the RV challenge.Patients with severe asthma had the highest levels of histamine-secreting M. morganii.27 Sphingolipids Experimental (mouse model) Sphingosine kinase inhibitor reduced inflammatory cell infiltrates, IL-4, IL-5, and eotaxin levels in BAL fluid, and suppressed airway hyperresponsiveness. 197 SPP-treated mice had increased mast cells and IL-4, IL-13, and IL-17 production in the lung.198 Case-control Children with non-allergic asthma had low levels of dihydroceramides, ceramides, and sphingomyelins.The results were inverse in children with allergic asthmatics.199 SPP levels were increased in asthmatics BAL fluid and modulated airway smooth muscle cell function.SPP inhibited TNF-α-induced RANTES release and induced IL-6 secretion.200 Baseline lung function and severity of airway hyperreactivity correlated with plasma SPP level in HDM allergic patients.Allergen challenge increased plasma SPP concentration.201 Atopic dermatitis SCFA Case-control & experimental (mouse model) Propionate content was lower on the skin surface of AD patients.Topical application of propionate attenuated skin inflammation in mice by inhibiting IL-33 production in keratinocytes and improved the symptoms of AD patients.154 AD patients had gut dysbiosis, dysregulated SCFA production, and increased IgE levels.Butyrate deficiency and downregulation of GPR109A and PPAR-γ genes were observed in a mouse model of AD. 155 Experimental (mouse model) Oral butyrate strengthened skin barrier function, limiting allergen penetration, allergic sensitization, and disease development.37 Sodium butyrate (SB) application in sensitized mice reduced the contact hypersensitivity reaction.SB upregulated foxp3 and IL-10 transcription.202 Experimental (human and mouse mast cell culture) Propionate and butyrate inhibited IgE-and non-IgE-mediated mast cell degranulation.203 Case-control AD was characterized by gut dysbiosis and depletion of butyrate-producing bacteria.

13 AD 177 Fructooligosaccharides
patients had decreased fecal levels of butyrate and propionate.153 Birth cohort Low fecal butyric acid was associated with an increased risk of developing wheezing, AD, and food sensitization till age 8 years.157 High levels of valeric acid at 3 years were associated with a low rate of eczema at the age of 8 years.158 Eczema at 13 years of age was negatively correlated with fecal valeric acid level at 1 year of age.159 Children with a lack of genes encoding enzymes for butyrate production develop allergic sensitization.lower in the lesional and nonlesional skin of patients with AD.IAId attenuated skin inflammation in mice.IAId inhibited TSLP expression in keratinocytes.Bifidobacterium longum treatment upregulated tryptophan metabolism and increased fecal and serum indole-3-carbaldehyde to reduce AD symptoms.162 Cross-sectional & experimental (cell culture) Tryptophan metabolism was altered in allergic subjects.Indole-3-butyric acid (IBA) and indole-3-lactic acid (ILA) inhibited LPS-induced upregulation of IL-4 and IL-6 in macrophages.43 Case-control AD patients had higher IDO-1 activity and neopterin, tryptophan, and kynurenine levels.195 Other metabolites Case-control Microbe-related methane and propanoate metabolisms were associated with AD.Metabolites dimethylamine and isopropanol were associated with host FLG mutations and serum IgE levels.204 Food allergy SCFAs Experimental (mouse model) SCFAs induced the proliferation of Treg cells and upregulated the expression of antiinflammatory cytokines.83 High-fiber diet protected against peanut allergy by reshaping the gut microbiome and increasing SCFA production.174 Case control SCFAs were lower in FA patients and correlated with less abundant Prevotella copri.172 Extensively hydrolyzed casein formula with probiotic Lactobacillus rhamnosus (EHCF þ LGG) promoted cow's milk allergy tolerance by influencing strain-level bacterial community and increasing the levels of fecal butyrate.176 Birth cohort Fatty acid metabolism was lower in the infant gut microbiome of children whose milk allergy resolved.173 Prospective cohort EHCF þ LGG treatment was associated with gut dysbiosis and butyrate production in non-IgE-mediated cow's milk allergy.175 Bile acids Experimental (mouse model) Bile acid-activated retinoic acid signaling promoted DC upregulation leading to Th2 differentiation of CD4 þ T cells.Depletion of bile acid reduced food allergen-specific IgE and IgG1 levels.28 Tryptophan Experimental (mouse model) Mice with FAs had increased tryptophan metabolism with higher levels of indole derivatives.improved allergic symptoms and regulated Th17/Treg balance by modulating gut microbiome and tryptophan metabolism.205 Case-control History of severe systemic reactions and the presence of multiple FAs were associated with changes in tryptophan metabolites, eicosanoids, plasmalogens, and fatty acids.patients have various systemic and skin immune abnormalities, including elevated serum IgE, sensitization to allergens, activated type 2 immune responses, and structural defect in skin-barrier Abbreviations: Aire, higher autoimmune regulator expressed in the medulla of the thymus; AW, allergy skin prick test and clinical wheeze data at 1 year of age; BAL, bronchoalveolar lavage; ECP, eosinophil cationic protein; FA, food allergy; HDM, house dust mite; HYA, 10-hydroxy-cis-12octadecenoic acid; IDId, Indole-3-aldehyde; IDO, indoleamine 2,3-dioxygenase; RV, rhinovirus; SCFA, short-chain fatty acid; SPP, sphingosine 1-phosphate; TLR, toll-like receptor; Treg, regulatory T cell.
Metabolites synthesized by the host or generated by the microbiome contribute to intestinal barrier integrity, immune metabolism, tolerance, activation of immune effector cells, and expression of proinflammatory cytokines and antimicrobial molecules.This review brings together the current literature on microbial metabolites in allergic diseases, identifying mechanisms triggered by microbial metabolites LOSOL ET AL.